Among viruses, human immunodeficiency virus (HIV), a kind of retrovirus, is known to cause acquired immunodeficiency syndrome (AIDS). The therapeutic agent for AIDS is mainly selected from the group of reverse transcriptase inhibitors (e.g., AZT, 3TC, and the like) and protease inhibitors (e.g., Indinavir and the like), but they are proved to be accompanied by side effects such as nephropathy and the emergence of resistant viruses. Thus, the development of anti-HIV agents having the other mechanism of action has been desired.
Under the above circumstance, the research has been focused on integrase, which is an enzyme relating to the site-specific recombination or insertion of viral DNA into chromosomes in animal cells, and the research for anti-HIV agents based on the enzyme inhibitory activity has been performed; (1) KOURILSKY P et al., Proc. Natl. Acad. Sci. USA 61 (3), 1013-1020 (1968); (2) F Barin et al., J. VIROL. METHODS (NETHERLANDS), 17/1-2(55-61) (1987); (3) Fesen. MR, Proc. Natl. Acad. Sci. USA 90: 2399, (1993); (4) DeNoon, DJ, CDC AIDS Weekly Pagination:P2 (1990). Some integrase inhibitors have recently been reported, for example, peptide derivatives described in U.S. Pat. No. 5,578,573, tetrahydronaphthyl derivatives described in GB 2306476A, and acrydone derivatives described in WO 97/38999.
Pyridine derivatives substituted with oxo propanoic acid are disclosed in J. Org. Chem. 1961 (26), p 4441. Quinoxaline derivatives substituted with oxo propanoic acid are disclosed in J. Chem. Soc. Chem. Commun. 1990, 23, p 1675-1676. Pyrazole derivatives substituted with oxo propanate ester are disclosed in Heterocycles, 1989, 29, p 1559. Pyridine, benzothiazole and pyrazine derivatives substituted with oxo propane acid ester are disclosed in Synth. Commun. 1992, 22(15), p 2245-2251. It is not disclosed in all the above documents that these compounds have an anti-HIV activity and anti-integrase inhibitory activity.
A combination therapy is reported to be efficient in treatment for acquired immunodeficiency syndrome against the frequent emergence of the resistant mutant in Balzarini, J. et al, Proc. Natl. Acad. Sci. USA 1996, 93, p 13152-13157. Reverse transcriptase inhibitors and protease inhibitors are clinically used as an anti-HIV agent but agents having the same mechanism of action often exhibit cross resistance or only an additional activity. Therefore, anti-HIV agents having the other mechanism of action are desired.